Differential Proliferation and Gene Expression In Langerhans Islets due to a lack of functional GABAB receptors

MARTÍN CRIVELLO; MARÍA MARTA BONAVENTURA; BERNHARD BETTLER; CARLOS LIBERTUN ; VICTORIA LUX-LANTOS

S. Francisco, CA

Congreso; The Endocrine Society (USA). 95th Annual Meeting, S. Francisco, CA Junio 15-18, 2013.; 2013

The Endocrine Socitey (USA)

Endocr Rev, Vol. 34 (03_MeetingAbstracts): SAT-850Copyright © 2013 by The Endocrine Society Premio: International Endocrine Scholars Program Awards. Differential Proliferation and Gene Expression In Langerhans Islets due to a lack of functional GABAB receptors Martin Crivello, MSc1, Maria Marta Bonaventura, PhD1, Bernhard Bettler, PhD2, Carlos Libertun, MDPhD3 and Victoria Adela Lux-Lantos, PhD4 1 Instituto de Biología y Medicina Experimental, Buenos Aires , Argentina2 Univ. of Basel, Basel , Switzerland3 IBYME-CONICET, Buenos Aires , Argentina4 IBYME, Buenos Aires , Argentina Differential Proliferation and Gene Expression In Langerhans Islets due to a lack of functional GABAB receptors Martín Crivello(1), María Marta Bonaventura(1), Bernhard Bettler (2), Carlos Libertun(1,3) and Victoria Lux-Lantos(1). (1)Neuroendocrinology Laboratory, IBYME-CONICET. (2)University of Basel, Basel, Switzerland. (3)School of Medicine, University of Buenos Aires, Argentina. martincrive@gmail.com During the past two decades the role of GABA in endocrine pancreas function has emerged as an increasingly active area of study (1). In our lab, we have previously demonstrated GABAB-receptor knock-out mice (KO) to suffer disruptions in glucose homeostasis (2). Here, aiming to better understand the role of said receptors in endocrine pancreas physiology and development, we evaluated, on the one hand, genetic expression of key islet genes (Ins1, Ins2, Gcg, Sst, Ppy, Gad1, Nes and Pdx1 via qPCR) in KO islets of newborn (4 days old) and adult (3-4 months old) mice. In the other hand we analyzed cellular composition and proliferation (immunohistochemical staining for PCNA, glucagon and insulin) and several physiological parameters (weight, glycemia, hormonal serum content and pancreatic hormonal content) in KO islets of newborn mice, in order to build up on our previous results for adults (3). We found an increased insulin content in pancreata from newborn female KO mice (~60%; Two-way ANOVA; interaction: p<0.05; KO females: different from all, p<0.05), like we had previously found in adult mice (3), though - unlike what was found in adults (3)- no insulin resistance was detected as scored by the HOMA-IR index at this early age. Furthermore, newborn KO mice showed a significant decrease in Ins2 (~60%), Sst (~55%) and Ppy (~45%) expression(Two-way ANOVA, interaction: NS; genotype: p<0.03), without differences for Nes or Pdx1. In contrast, adult KO females had an increased expression of Ins1 (~100%), Ins2 (~250%) and Sst (~200%) genes vs their WT litter-mates (Two-way ANOVA; interaction: p<0.05; for Ins1 and Ins2: different from WT females, p<0.05; for Sst: different from WT females and KO males: p<0.03). Pdx1 had a higher expression in adult KO mice of both genders (~60% for males and ~300% for females; two-way ANOVA, interaction: NS; genotype: p<0.04). This marked increase of Pdx1 expression in female mice could be the driving force behind the increased expression of Ins and Sst, which are known to respond to PDX1. Finally, we also found that newborn KO mice had diminished proliferation of both a and b cells in endocrine clusters, in contrast to the increased proliferation found in adult KO females. No differences where found in the proliferation indexes of the islet population between all genders and genotypes. In all, these results contribute more insight on how GABAB receptors may be involved in key aspects of normal islet physiology. (CONICET, UBA, ANPCYT) 1. Franklin IK, Wollheim CB. 2004. GABA in the endocrine pancreas: its putative role as an islet cell paracrine-signalling molecule. J Gen Physiol. 123(3):185-90. 2. Bonaventura MM, Catalano PN, Chamson-Reig A, Arany E, Hill D, Bettler B, Saravia F, Libertun C, Lux-Lantos VA. 2008. GABAB receptors and glucose homeostasis: evaluation in GABAB receptor knockout mice. Am J Physiol Endocrinol Metab. 294:E157-E167 3. Martin Crivello, María Bonaventura, Bernhard Bettler, Carlos Libertun, Victoria Lux-Lantos. 2011. Effects on pancreas alpha and beta cell composition and glutamate decarboxylase expression due to lack of functional GABAB receptors. ENDO Abstract. Endocrine Reviews Vol. 32(3):P2-478. Nothing to Disclose: MC, MMB, BB, CL, VAL *Please take note of The Endocrine Society?s news embargo policy at www.endo-society.org/endo2013/media.cfm Sources of Research Support: CONICET, UBA, ANPCYT